Abstract

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The majority (75%) of human breast cancers express estrogen receptor (ER). Although ER-positive tumors usually respond to anti-estrogen therapies, 30% of them do not. It is not known what controls the ER status of breast cancers or their responsiveness to anti-hormone interventions. In this report, we document that transgenic expression of Wnt-1 in mice induces ER-positive tumors. Loss of Pten or gain of Ras mutations during the evolution of tumors in Wnt-1 transgenic mice has no effect on the expression of ER, but overexpression of Neu or loss of p53 leads to ER-negative tumors. Thus, our results provide compelling evidence that expression of ER in breast cancer may be influenced by specific genetic changes that promote cancer progression. These findings constitute a first step to explore the molecular mechanisms leading to ER-positive or ER-negative mammary tumors. In addition, we find that ER-positive tumors arising in Wnt-1 transgenic mice are refractory to both ovariectomy and the ER antagonist tamoxifen, but lose ER expression with either treatment, suggesting that these treatments select for ER- tumor cells and that the ER+ cell fraction is dispensable for growth of these tumors. This is a first report of a mouse model of anti-estrogen resistant ER+ breast cancers, and could provide a powerful tool to study the molecular mechanisms that control anti-estrogen resistance.